14-67724588-C-T
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_152443.3(RDH12):c.184C>T(p.Arg62Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000776 in 1,611,290 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R62R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_152443.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RDH12 | NM_152443.3 | c.184C>T | p.Arg62Ter | stop_gained | 4/9 | ENST00000551171.6 | |
RDH12 | XM_047430965.1 | c.184C>T | p.Arg62Ter | stop_gained | 4/9 | ||
GPHN | XM_047430879.1 | c.1313-10607C>T | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RDH12 | ENST00000551171.6 | c.184C>T | p.Arg62Ter | stop_gained | 4/9 | 1 | NM_152443.3 | P1 | |
RDH12 | ENST00000267502.3 | c.184C>T | p.Arg62Ter | stop_gained | 3/8 | 5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000723 AC: 11AN: 152068Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000557 AC: 14AN: 251424Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135904
GnomAD4 exome AF: 0.0000781 AC: 114AN: 1459104Hom.: 0 Cov.: 31 AF XY: 0.0000661 AC XY: 48AN XY: 726006
GnomAD4 genome AF: 0.0000723 AC: 11AN: 152186Hom.: 0 Cov.: 31 AF XY: 0.0000403 AC XY: 3AN XY: 74398
ClinVar
Submissions by phenotype
Leber congenital amaurosis 13 Pathogenic:8
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Pathogenic, no assertion criteria provided | research | Laboratory of Genetics in Ophthalmology, Institut Imagine | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 22, 2021 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 2004 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 18, 2023 | This sequence change creates a premature translational stop signal (p.Arg62*) in the RDH12 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RDH12 are known to be pathogenic (PMID: 17964524, 22065924, 32014858, 34001834). This variant is present in population databases (rs104894471, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with autosomal recessive Leber congenital amaurosis or retinitis pigmentosa (PMID: 15258582, 15322982, 26497376, 29186038). ClinVar contains an entry for this variant (Variation ID: 2050). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 27, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Jul 22, 2022 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Ocular Genomics Institute, Massachusetts Eye and Ear | Aug 01, 2019 | - - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 15, 2019 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in 4/24,014 (0.017%) alleles from individuals of African background and in 13/277,094 (0.005%) global alleles, in large population cohorts and no individuals were reported to be homozygous (Lek et al., 2016); This variant is associated with the following publications: (PMID: 32865313, 31054281, 30134391, 29186038, 15258582, 29068479, 15322982, 26497376) - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Leber congenital amaurosis Pathogenic:2
Pathogenic, criteria provided, single submitter | research | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | May 29, 2020 | The heterozygous p.Arg62Ter variant in RDH12 was identified by our study in 1 individual with Leber congenital amaurosis, in a compound heterozygous state with a likely pathogenic variant. Please note that this variant has been identified by a collaborative research study and was also be submitted by Massachusetts Eye and Ear. The p.Arg62Ter variant has been reported in at least 10 individuals with Leber congenital amaurosis (PMID: 15322982,15258582, 29186038, 32014858, 26497376, 30134391). The presence of this variant in at least 2 homozygotes, and in combination with a reported pathogenic variant, and in at least 1 individual with Leber congenital amaurosis increases the likelihood that the p.Arg62Ter variant is pathogenic (PMID: 15258582, 26497376, 30134391) and has been identified in 0.016% (4/24952) of African, 0.009% (11/129094) of European (Non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs104894471). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar as pathogenic by Mendellics, Invitae, OMIM, Ocular Genomics Institute, Massachusetts Eye and Ear, Blueprint Genetics (VariationID: 2050). This nonsense variant leads to a premature termination codon at position 62, which is predicted to lead to a truncated or absent protein. Loss of function of the RDH12 gene is a moderately established disease mechanism in autosomal recessive Leber congenital amaurosis. The p.Arg62Ter variant is located in a region of RDH12 that is essential to protein folding and stability, suggesting that this variant is in a functional domain and slightly supports pathogenicity (PMID: 32014858). In summary, this variant meets criteria to be classified as pathogenic for Leber congenital amaurosis in an autosomal recessive manner based on the predicted loss of function effect of this variant and the presence of this variant in the homozygous state and in combination with other pathogenic variants in affected individuals. ACMG/AMP Criteria applied: PVS1_strong, PM1_supporting, PM3_strong (Richards 2015). - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Dec 04, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at